The present invention relates to an anti-proteolytic composition useful in the treatment of protein wasting disorders. In particular, the present invention relates to compositions useful in the treatment of muscle wasting disorders and intracellular protein degradation disorders of mammalian skeletal muscle systems.
Tetracyclines constitute a family of well known natural and synthetic broad spectrum antibiotics. The parent compound, tetracycline, exhibits the following general structure: ##STR1##
The numbering system of the ring nucleus is as follows: ##STR2##
Tetracycline as well as the 5-OH (terramycin) and 7-Cl (Aureomycin) derivatives exist in nature, and are well known antibiotics. Natural tetracyclines may be modified without losing their antibiotic properties, although certain elements of the structure must be retained. The modifications that may and may not be made to the basic tetracycline structure have been reviewed by Mitscher in The Chemistry of Tetracyclines, Chapter 6. According to Mitscher, the substituents at positions 5-9 of the tetracycline ring system may be modified without the complete loss of antibiotic properties. Changes in the basic ring system or replacement of the substituents at positions 1-4 and 10-12, however, generally lead to synthetic tetracyclines with substantially less or effectively no antibacterial activity. For example, 4-dedimethylamino-tetracycline is commonly considered to be a non-antibacterial tetracycline.
Various properties of antimicrobial and non-antimicrobial tetracyclines are known. Most commonly known is the bacteriostatic activity of the antimicrobial tetracyclines. Additionally, both antimicrobial and non-antimicrobial tetracyclines are known inhibitors of collagen degrading enzymes such as mammalian collagenase, macrophage elastase and bacterial collagenase; Golub, et al., J. Periodont. Res. 20, 12-23 (1985) and Golub, et al., J. Periodont. Res. 1990, in press. Collagen is a major component of connective tissue matrices such as those in bone, synovium, eye, skin, tendons and gingiva. Collagenase, which is naturally produced by only a few types of bacteria and in a number of tissues and cells in mammals, degrades collagen.
U.S. Pat. No. 4,704,383 to McNamara, et al. discloses that tetracyclines having substantially no effective antibacterial activity inhibit collagenolytic enzyme activity in rats. McNamara, et al. also report that non-antimicrobial tetracyclines reduce bone resorption in organ culture.
Earlier, U.S. Pat. No. 4,666,897 to Golub, et al. disclosed that tetracyclines in general, including commercially-available antimicrobial forms of the drug, inhibit excessive bone resorption and collagenolytic enzyme activity.
The effects of tetracyclines on rates of degradation of intracellular proteins has not been investigated. In particular, the effects of these agents on rates of degradation of skeletal muscle intracellular proteins has not been reported. Therefore, an effect of tetracyclines has not been established, however, for mammals with skeletal muscle wastinq or disorders of the mammalian skeletal muscle system characterized by intracellular protein degradation.
In humans, there is a variety of disorders in which protein wasting in skeletal muscles and intracellular protein degradation in skeletal muscle play a prominent role. Examples of such diseases include uncontrolled diabetes mellitus, cachexia of cancer, acquired immune deficiency syndrome (AIDS), burns, trauma, etc. Muscle wasting and protein degradation result in muscle weakness, fatigue and loss of function.
Insulin, naturally occurring in mammals, and the mainstay of treatment for hyperglycemia, is known to inhibit protein degradation and stimulate protein synthesis in the skeletal muscle system of mammals. While useful in the treatment of the hyperglycemic disease, diabetes mellitus, the use of insulin in non-hyperglycemic mammals having diseases associated with muscle wasting and/or protein degradation can be lethal, because the potent hypoglycemic action of insulin severely limits its use as an anti-proteolytic in non-hyperglycemic mammals.
Oral hypoglycemics, such as glyburide, have also been shown to have an anti-proteolytic effect similar to that of insulin. Co-inventors herein, Gorray, Maimon and Schneider disclose significant depression of protein degradation by using glyburide on rat L.sub.6 myoblasts, Metabolism 39, No. 2, 109-116 (1990). Oral hypoglycemics, however, like insulin, are impracticable as antiproteolytic agents in non-hyperglycemic mammals.
It is therefore an object of the present invention to provide a method useful in the treatment of skeletal muscle wasting and muscle intracellular protein degradation disorders which does not suffer from the drawbacks of the methods disclosed above which rely upon administering hypoglycemic agents.
It is a further object of the present invention to provide a method of promoting protein synthesis in skeletal muscle systems exhibiting excessive proteolytic action.